Excess dietary salt is a major contributing factor to the incidence and severity of hypertension. However, the precise mechanism(s) by which salt contributes to the severity of hypertension are unknown. The region of the rostral ventrolateral medulla (RVLM) is a principal brain stem locus critical for the regulation of arterial blood pressure by the central nervous system (CNS). Recent studies from this laboratory have shown that excess dietary salt (NaCl) consumption specifically sensitizes vasomotor neurons of the RVLM to excitatory stimulation. The long-term objective of this research is to determine if salt-sensitization of the RVLM contributes to the pathogenesis of hypertension. The proposed research will provide convergent lines of evidence to address this question. The first Specific Aim will be to parametrically characterize and establish the conditions necessary to produce salt-sensitization of the RVLM. This will be accomplished by feeding rats various concentrations of NaCl in the diet and measuring pressor and sympathoexcitatory responses produced by activation of RVLM neurons using microinjections of L-glutamate. The second Specific Aim will identify CNS mechanisms that contribute to salt- sensitization of the RVLM. Responses produced by RVLM microinjections of receptor-selective drugs will establish whether pressor and sympathoexcitatory responses of rats consuming excess NaCl are uniformly augmented, or whether response potentiation is associated with specific neurotransmitter receptors. It will also be determined if brain lesions known to prevent salt-dependent hypertension also prevent salt sensitization of RVLM vasomotor neurons. The third Specific Aim will examine the relationship of salt-sensitization of the RVLM to salt- dependent experimental hypertension. This will be accomplished by measuring cardiovascular and sympathoexcitatory responses produced by stimulation of the RVLM in hypertensive rats, and determining whether chronic destruction of RVLM neurons can prevent the development of salt- dependent hypertension. The proposed studies will be among the first to extend to pathological conditions what is known of RVLM function in normotensive animals; and will contribute significantly to our understanding of the relationship between dietary salt, hypertension, and the brain.